Three-dimensional model of the cyclin-dependent kinase 1 (CDK1): Ab initioactive site parameters for molecular dynamics studies of CDKs

Cyclin-dependent kinase 1 (CDK1) is an interesting target for potential ant icancer drugs, and its three-dimensional (3D) structure is presently unknow n. The purpose of this work was to build a 3D model of CDK1, which could be used in drug design studies. The protein 3D structure was homology modeled , based on the known crystal structure of CDK2, and new nonbonded parameter s for the Mg2+ coordination complex were developed by means of ab initio qu antum chemical calculations. These parameters were both obtained and valida ted using the CDK2 structure as reference, and then they were used for the refinement of the CDK1 model. The resulting CDK1 structure was satisfactory and stable at room temperature, as shown by the molecular dynamics simulat ions carried out over a I-ns time interval on the entire protein. A number of representative kinases in the active and inactive form, including the in active CDK1 modeled in this work, were compared. The results illustrate the conformational variability of the activation loop of the inactive form of the kinases and suggest a way for selectively targeting the single CDKs. (C ) 2001 Wiley-Liss, Inc.